As it has been shown that the volume of the extracellular compartment of the brain of a senescent rat is about half that of a young adult we are attempting to characterize age-related changes in the neuronal microenvironment and to define their histophysiological implications. We have proposed an analysis of the ultrastructural histochemistry of the brain extracellular compartment correlated with biochemical analysis of brain acidic glycans. The capacity of extracellular channels to react with ruthenium red appears lessened in the senescent brain suggesting an age-related change in charge density of the neuronal microenvironment. We are investigating the contribution to this change in charged macromolecules associated with neuronal plasma membrane and those which are believed to comprise the extracellular substance of brain. Our studies of glycoproteins of neuronal plasma membrane are based upon the capacity of the membrane to combine with conconavalin A. Nerve cells isolated from the lateral vestibular nucleus of young adult and senescent rats are incubated with fluorescamine-labelled conconavalin A and binding capacity is evaluated by means of fluorescence microscopy. Acidic glycans, presumably constituents of the extracellular substance of brain tissue, are being analyzed biochemically with regard to their synthesis, metabolism and intracellular transport. To date these analytical studies show an age-related increase in sulfate concentration and in the sulfate/hexosamine mole ratio.